A group of 93 rhesus monkeys has been made diabetic by streptozotocin injection (48 animals) or total pancreatectomy (45 animals). These animals have been observed up to 12 years after diabetes induction for development of acute (96 h), short-term (less than 2 years), and long-term physiologic and morphologic changes in the eye, kidney and pancreas. These studies show that precisely those changes which occur initially in human insulin-deficient diabetes, including varying degrees of insulin reserve, ketosis, hyperglucagonemia, glycohemoglobin elevations, breakdown of the blood-retinal barrier, renal hyperfunction and proteinuria, glomerular hypertrophy, mesangial proliferation and expansion, glomerular capillary BM thickening, and altered pancreatic endocrine populations, also occur in the diabetic monkey. However, despite the long duration of severe diabetes in many animals, end stage diabetic micro- or macroangiopathy has not been observed. We hypothesize that the development of irreversible end stage diabetic microangiopathy of the kidney and eye may require not only the presence of structural and functional abnormalities caused by hyperglycemia and insulin deficiency, but also a series of insults and injury caused by hyperlipidemia and hypertension. We will study the development and progression of renal and ophthalmic lesions by inducing hyperlipidemia and hypertension in order to assess the relative importance of these risk factors alone or together in diabetic monkeys. Reversal of these treatments will allow examination of regression of the induced lesions. These studies will use measurements of glycosylated hemoglobin, vitreous fluorophotometry, renal function, proteinuria, histopathology of eye and kidney, and morphometric analysis of glomeruli. In addition, we will continue to gather data concerning the natural history of insulin deficiency in the monkey and shall continue our studies of rhesus histocompatibility and islet isolation.